GNB4

Inheritance Pattern: AD

Disease ID:MONDO:0015626

Submitter: ClinGen

GNB4 was first reported in relation to autosomal dominant Charcot-Marie-Tooth Disease in 2013 (Soong et al., PMID: 23434417). Reported cases to date have an adolescent onset and are further characterized by slowly progressive distal muscle atrophy and weakness, distal sensory impairment with decreased reflexes, and variable nerve conduction velocities ranging from the demyelinating to the axonal range. Four missense variants, two of which are de novo, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least four probands in three separate publications (PMIDs: 23134117, 28642160, 27908631). Variants in this gene segregated with disease in five additional family members in one large family. Although the initial characterization evidence to support pathogenicity, there is a lack of appropriate supporting evidence for the latter two cases. This gene-disease relationship is additionally supported by expression data and functional alteration of human oligodendrocyte progenitor cells (hOPCs). Investigation determined that GNB4 is largely expressed in axons and Schwann cells of neurons, relating to the neurodegenerative phenotypes characteristic of CMT. Additionally, mice with an immunodeficient, demyelinating phenotype were injected with hOPCs both expressing and not expressing GNB4 and found a large increase in the latter's differentiation compared to the controls, suggesting a major role in myelin development and differentiation. Although there is additional evidence available, the lack of the exact mechanism and an animal model limits the scorable data. In summary, there is MODERATE evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Charcot-Marie-Tooth Expert Panel on 02/25/20 (SOP Version 007). **Recuration update**: Four additional unrelated families from two publications were curated, providing new genetic evidence supporting the association between GNB4 and autosomal dominant Charcot-Marie-Tooth disease. Kwon et al. (2021; PMID: 34071515) reported three unrelated Korean families carrying heterozygous GNB4 variants. One family harbored the novel c.229G>A (p.Gly77Arg) variant, which occurred de novo in a patient with intermediate CMT and was absent from both unaffected parents. Although no variant-specific functional studies were performed, the phenotype was highly consistent with GNB4-associated neuropathy, and the variant affected a highly conserved residue within the WD40 repeat domain. This proband was scored as 1.0 point. Two additional unrelated families carried the recurrent c.265A>G (p.Lys89Glu) variant, each arising independently as a de novo event. This variant had previously been established as pathogenic and was supported by published functional studies demonstrating impaired GPCR signaling. Given the independent de novo occurrences of a recurrent pathogenic variant and the highly specific neuropathy phenotype, each family was scored as 1.5 points, contributing a total of 4.0 genetic evidence points. Pretkalnina et al. (2025; PMID: 41164122) described an additional unrelated autosomal dominant family carrying the novel c.239T>C (p.Ile80Thr) variant. The variant segregated with disease in multiple affected family members and was supported by extensive variant-specific functional studies demonstrating reduced Gβ4 protein expression, abnormal intracellular localization, and impaired GPCR signaling with significantly reduced IP₁ production. Based on the segregation data, highly consistent phenotype, and strong functional evidence, this family was scored as 1.0 point. Together, these publications contributed five additional genetic evidence points, increasing the total genetic evidence score further strengthening the association between GNB4 and autosomal dominant CMT. The total evidence reached 10.6 points which is still equivalent to Moderate classification, although the evidence remains just below the threshold for a definitive classification

Inheritance Pattern: AD

Disease ID:MONDO:0014074

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014074

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014074

Submitter: Labcorp Genetics (formerly Invitae)